# Molecular mechanisms of allele-specific NRAS signaling and tumorigenesis

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $640,969

## Abstract

ABSTRACT
Cancer-associated RAS mutants were once considered oncogenic equivalents. However, it is increasingly clear
that mutants of the same RAS isoform (H-, K- or NRAS) and amino acid (codon 12, 13) can exhibit distinct
GTPase, effector binding, signal transduction, and tumorigenic properties. These distinctions may contribute to
disparities in therapeutic response as well as the enrichment of specific RAS isoforms and amino acid
substitutions in each cancer type. Thus, a deeper understanding of how each amino acid substitution influences
RAS structure, biochemistry, and function could yield meaningful biological and clinical advances.
KRAS mutants are well-studied, but whether the biochemical consequences of an amino acid change in one
RAS isoform can be extended to another is unclear. In particular, research into the mutant-specific functions of
NRAS, the dominant RAS oncoprotein in thyroid cancer, acute myeloid leukemia, and melanoma, is limited.
Here, we examine the ability of eight different oncogenic NRAS oncoproteins to induce spontaneous melanoma
in mouse models. We find that oncogenic substitutions, even in the same amino acid of NRAS, have distinct
melanomagenic potential. Our preliminary data link the greater melanomagenic potential of these mutants to
structural features that enhance BRAF affinity, activation, and Mitogen-activated protein kinase (MAPK)
signaling. These observations are consistent with studies linking increasing MAPK activity to melanoma
progression in human nevi. Furthermore, we provide evidence that current knowledge of KRAS mutants cannot
be translated to NRAS. Based on these data, we hypothesize that melanoma formation depends on
substitution- and isoform-specific structural differences in NRAS that enhance BRAF dimerization and
MAPK>ERK signaling. In Aim 1, we propose integrated X-ray, NMR, computational, and biochemical
approaches to determine the structural ensembles and biochemical properties of NRAS oncoproteins of varying
melanomagenic potential and compare these profiles to similar KRAS mutants. In Aim 2, we describe a
combination of structural, biochemical, and live-cell reporter experiments to determine how NRAS mutants
differentially recognize and promote BRAF activation. In Aim 3, we will test the concept that a transient
pharmacological approach could prevent melanoma by eliminating NRAS-mutant cancer precursors with
elevated MAPK>ERK signaling from the skin.
If successful, these studies will uncover distinguishing structural and biochemical features of the NRAS
oncoproteins that may lead to the identification of new interfaces for drug targeting, determine the molecular
basis for NRAS-driven melanomagenesis, elucidate RAS isoform-specific mechanisms of RAF activation, and
test a potential prevention strategy for NRAS-mutant melanoma.

## Key facts

- **NIH application ID:** 10980720
- **Project number:** 1R01CA287193-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Christin E Burd
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $640,969
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980720

## Citation

> US National Institutes of Health, RePORTER application 10980720, Molecular mechanisms of allele-specific NRAS signaling and tumorigenesis (1R01CA287193-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10980720. Licensed CC0.

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